OP0117 PROTEASOME INHIBITION AS A NEW TREATMENT FOR DERMATOMYOSITIS: RESULTS OF A DRUG REPURPOSING ANALYSIS BASED ON THE TRANSCRIPTOMIC SIGNATURE OF PATIENTS’ PERIFASCICULAR FIBERS VALIDATED IN PRE-CLINICAL MODELS
Authors: L. Debrut, M. Giannini, C. Keime, D. Rovito, P. Mertz, B. Lannes, A. L. Charles, D. Metzger, B. Geny, G. Laverny, A. Meyer
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Dermatomyositis (DM) is an autoimmune myopathy responsible for muscle weakness associated with decreased quality of life and increased mortality. Current treatments are empirical, partially effective, expose to a risk of side effects and a high rate of relapse upon discontinuation. DM muscular histology is characterized by lesions of perifascicular fibers consisting of atrophy, overexpression of type I interferon-dependent genes and mitochondrial dysfunctions of unknown origin [1]. <h3>Objectives</h3> The objective of the study was to identify innovative therapeutic strategies for DM, based on the identification of the molecular pathways that underlie perifascicular fibers lesions and the repositioning of drugs already approved in humans. <h3>Methods</h3> To reveal the molecular pathways underlying DM perifascicular fibers lesions, perifascicular and endofascicular fibers from 19 patients with recent and untreated myositis (DM, other myositis) or without myopathy were microdissected by laser, their transcriptome was established by RNA sequencing and analyzed by bioinformatic methods. To identify innovative therapeutic strategies based both on DM pathophysiological mechanisms and on existing drugs, the transcriptomic signature specific to DM perifascicular fibers obtained by microdissection experiments was used for a drug repositioning analysis as described by Karatzas et al. [2]. To validate the predications obtained, the effect of drug candidates already used in humans was tested in <i>in vitro</i> and <i>in vivo</i> preclinical models: in 1) cultured human muscle cells treated with IFN-I and in 2) a mouse model of myositis experimentally induced by immunization against skeletal muscle fast-type C protein. <h3>Results</h3> Transcriptomic analysis of patient's muscle fibers combined with topographic information (perifascicular VS endofascicular localization) revealed that a proteasome deregulation predominant in the perifascicular fibers is a hallmark of DM. The integration of 3 computer databases of drug repositioning allowed the identification of 9 molecules predicted by at least 2 bases to reverse the pathological signature of the perifascicular fibers of patients with DM. The drug with the highest therapeutic potential was a proteasome inhibitor (Ixazomib). A second proteasome inhibitor (MG-132) was also identified. 2 drugs already used for DM (prednisolone and a JAK inhibitor) was identified with a lower therapeutic score. In the cellular model (human myotubes treated with IFN-I) ixazomib and bortezomib reversed the atrophy and the pathological signature of DM perifascicular fibers identified in the microdissection experiments. In the mouse model of myositis, ixazomib and bortezomib restored muscle strength, decreased blood creatine kinase, and reversed the atrophy of muscle fibers. <h3>Conclusion</h3> Proteasome inhibition could be a new effective therapeutic strategy for DM. <h3>References</h3> [1]Meyer et al. 2017. IFN-β-Induced Reactive Oxygen Species and Mitochondrial Damage Contribute to Muscle Impairment and Inflammation Maintenance in Dermatomyositis. <i>Acta Neuropathol.</i> 134 (4): 655-66. [2]Karatzas et al. 2019. An Application of Computational Drug Repurposing Based on Transcriptomic Signatures. Methods Mol Biol 1903, 149-177. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.